Topically administrable pharmaceutical preparations

ABSTRACT

The invention relates to topically adminstrable pharmaceutical preparations containing pharmaceutically acceptable methanediphosphonic acid derivatives of formula ##STR1## and their salts, wherein each of R 1  and R 2  is halogen, or wherein R 1  is hydrogen and R 2  is Ar--S-- or Het 1  --NH--, in which Ar is unsubstituted or substituted phenyl and Het 1  is unsubstituted or substituted, monocyclic, 5- or 6-membered monoaza-, diaza- or thiaza-aryl that is bonded via a ring carbon atom, or wherein R 1  is hydrogen or hydroxy and R 2  is --A--R 3 , in which A is alkylene and, on the one hand, R 3  is Het 2 , which is Het 1  bonded via a ring carbon or ring nitrogen atom, or, on the other hand, R 3  is hydrogen, or amino that is unsubsituted or mono- or di-substituted by identical or different substituents selected from alkyl, cycloalkyl, Ar-alkyl, Ar-O-alkyl, Ar-S-alkyl and Het 1  -alkyl, or that is disubstituted by optionally Ar-containing alkylene, wherein two alkylene carbon atoms mar additionally be linked to one another via alkylene and Ar and Het 1  are each as defined above, with the proviso that when R 2  is --A--R.sub. 3, A is ethylene and R 3  is unsubstituted or C 1  -C 3  alkyl-substituted amino, R 1  is other than hydroxy.

It is known that representatives of a class of syntheticmethanediphosphonic acid derivatives are used, for example, in thetreatment of osteolytic bone metastases and hypercalcaemia, since theyare able to inhibit the growth and decomposition of hydroxyapatite.These compounds thus prevent bone resportion by binding spontaneously tothe hydroxyapatite of the bone, so that osteoclasts, for example, areunable to cleave further hydroxyapatite crystals. Compounds of thisclass of substances are described, for example, in DE-OS 2,405,254.

It is known that corresponding methanediphosphonic acid derivatives areabsorbed to only a small extent following oral administration,especially if food is given at the same time. In order to achieve thedesired therapeutic effect, correspondingly higher doses must beadministered.

Because of the importance of this class of substances in the treatmentof, for example, osteoporosis, Paget's disease, Bechterew's disease andthe formation of bone metastases, many attempts are being made toprovide a pharmaceutical form of administration from which the activeingredients can readily be absorbed irrespective of whether food isgiven.

The methanediphosphonic acid derivatives used in accordance with theinvention, which contain two dissociable acid groups and a basic centre,are known to exist in ionic form. F. N, Marzulli et al., The Journal ofInvestigative Dermatology 44, 339-344 (1965), studied the penetration ofradioactively labelled organic phosphoric acid esters and phosphoricacid in vitro through human Stratum corneum and found that ionisedphosphoric acid is able to pass through the skin to only anextraordinarily small extent. The conclusion drawn from these studieswas that neutral molecules pass through the barrier of the Stratumcorneum relatively easily, while ionic forms are able to penetrate onlyto a very small extent and with great difficulty. This view is shared byR. J. Scheuplein, Physiological Reviews 51, 16-23 (1971), who concludesthat ionisation drastically reduces skin permeation.

Even more surprising is the discovery that pharmaceutically acceptablemethanediphosphonic acid derivatives, especially those of formula Ibelow, are readily conveyed through the skin and can thus immediatelyact systemically. These unexpected discoveries were made during in vitrostudies to determine percutaneous absorption properties by the method ofA. S. Bhatti et al., J. Pharm. Pharmacol., 40, 45 P (1988). In thesestudies, corresponding diffusion cells having a cell surface area of1.27 cm² and pig skin as the membrane were used as a model for humanskin. The studies showed that significant therapeutic amounts of activeingredient diffused through the membrane. These results were confirmedin studies of the in vivo transdermal absorption of bisphosphonates.Experiments were carried out on guinea pigs using ¹⁴ C-labelled activeingredient. 6 mg of cold bisphosphonate active ingredient andapproximately 10⁶ dpm of ¹⁴ C-labelled bisphosphonate in 200 μl of 2%Klucel in distilled water having a pH of 7.5 were applied to a shavedarea of 3×5 cm, and the area was covered with an occlusive dressing. Theradioactive material in the excreted urine was measured after 1, 2 and 3days.

The present invention relates to topically administrable pharmaceuticalpreparations containing pharmaceutically acceptable methanediphosphonicacid derivatives or salts thereof, to their manufacture and use:

Suitable methanediphosphonic acid derivatives having pharmaceuticalactivity are, for example, compounds of formula ##STR2## and theirsalts, wherein each of R₁ and R₂ is halogen, or wherein R₁ is hydrogenand R₂ is Ar--S-- or Het₁ --NH--, in which Ar is unsubstituted orsubstituted phenyl and Het₁ is unsubsituted or subsituted, monocyclic,5- or 6-membered monoaza-, diaza- or thiaza-aryl that is bonded via aring carbon atom, or wherein R₁ is hydrogen or hydroxy and R₂ is--A--R₃, in which A is alkylene and, on the one hand, R₃ is Het₂, whichis Het₁ bonded via a ring carbon or ring nitrogen atom, or, on the otherhand, R₃ is hydrogen, or amino that is unsubstituted or mono- ordi-substituted by identical or different substituents selected fromalkyl, cycloalkyl, Ar-alkyl, Ar-O-alkyl, Ar-S-alkyl and Het₁ -alkyl, orthat is disubstituted by optionally Ar-containing alkylene, wherein twoalkylene carbon atoms may additionally be linked to one another viaalkylene and Ar and Het₁ are each as defined above, with the provisothat when R₂ is --A--R₃, A is ethylene and R₃ is unsubstituted or C₁ -C₃alkyl-substituted amino, R₁ is other than hydroxy.

Salts of compounds of formula I are especially their salts with bases,such as metal salts derived from groups Ia, Ib, IIa and IIb of thePeriodic Table of Elements, for example alkali metal salts, especiallysodium or potassium salts, alkaline earth metal salts, especiallycalcium or magnesium salts, and also ammonium salts with ammonia ororganic amines.

Substituted phenyl is mono- or poly-substituted, for example di- ortri-substituted, for example by lower alkyl, lower alkoxy,trifluoromethyl and/or, especially, by halogen.

Monocyclic, 5- or 6-membered monoaza-, diaza- or thiaza-aryl is, forexample, pyrrolyl, imidazolyl, such as 1-, 2- or 4-imidazolyl,pyrazolyl, such as 1- or 3-pyrazolyl, thiazolyl, such as 2- or4-thiazolyl, or pyridyl, such as 2-, 3- or 4-pyridyl. Correspondingradicals may be mono- or poly-substituted, for example di- ortri-substituted, for example by alkyl. Preferred substituted radicalsare, for example, imidazol-1-yl and imidazol-5-yl, 5-loweralkylthiazol-2-yl, such as 5-methylthiazol-2-yl, 5-ethylthiazol-2-yl and5-n-butylthiazol-2-yl, and 2- and 3-pyridyl.

Alkyl is especially lower alkyl and alkylene is especially loweralkylene, while Ar-alkyl is, for example, phenyl-lower alkyl which isunsubstituted or substituted in the phenyl moiety as indicated above.

Cycloalkyl is especially C₃ -C₇ -cycloalkyl, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Amino that is mono- or di-substituted by alkyl, cycloalkyl, Ar-alkyl,Ar-O-alkyl, Ar-S-alkyl or by Het₁ -alkyl is especially lower alkylamino,C₃ -C₇ -cycloalkylamino, phenyl-lower alkylamino, di-lower alkylamino,lower alkylphenyl-lower alkylamino, diphenyl-lower alkylamino,phenoxy-lower alkylamino, lower alkylphenoxy-lower alkylamino,phenoxy-lower alkylphenyl-lower alkylamino, diphenoxy-lower alkylamino,phenylthio-lower alkylamino, lower alkylphenylthio-lower alkylamino,phenylthio-lower alkylphenyl-lower alkylamino, diphenylthio-loweralkylamino, lower alkylpyridyl-lower alkylamino, phenyl-loweralkylpyridyl-lower alkylamino, phenoxy-lower alkylpyridyl-loweralkylamino, phenylthio-lower alkylpyridyl-lower alkylamino ordipyridyl-lower alkylamino, the phenyl or pyridyl moiety beingunsubstituted or substituted as indicated above.

Amino that is disubstituted by optionally Ar-containing alkylene, forexample 1,4-butylene or 1,5-pentylene, is especially lower alkyleneaminoor lower alkyleneamino containing a phenyl radical that is unsubstitutedor substituted as indicated above, such as pyrrolidin-1-yl,2-(4-chlorophenyl)-1,4-butyleneamino or 3-phenyl-1,5-pentyleneamino.

Amino that is disubstituted by alkylene wherein two alkylene carbonatoms are additionally linked to one another via alkylene is especiallylower alkyleneamino wherein two lower alkylene carbon atoms, especiallynon-adjacent atoms, are linked to one another via lower alkylene,especially methylene. Preferred are, for example, corresponding3-azabicyclo-C₆ -C₁₀ alk-3-yl radicals.

The general definitions used hereinbefore and hereinafter, unlessdefined otherwise, have especially the following meanings, radicals orcompounds designated "lower" containing especially up to and including 7carbon atoms:

Halogen is especially halogen having an atomic number of up to andincluding 35, such as fluorine or bromine and also iodine, especiallychlorine.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec.-and tert.-butyl, and also includes correspondingpentyl, hexyl and heptyl radicals. C₁ -C₄ alkyl is preferred.

Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy andn-butoxy, and also includes corresponding pentyloxy, hexyloxy andheptyloxy radicals. C₁ -C₄ alkoxy is preferred.

Lower alkylene is straight-chain or branched and is, for example, C₁ -C₇alkylene, such as methylene, ethylene, propylene, butylene, pentyleneand hexylene and heptylene, and also 2-methyl-1,3-propylene and 2,4- or1,5-dimethyl-1,5-pentylene. Lower alkylene as a substituent ofdisubstituted amino R₃ contains at least two carbon atoms, preferablyfrom 4 to 6 carbon atoms. In amino that is disubstituted by loweralkylene, lower alkylene linking two lower alkylene carbon atomscontains especially up to and including 5 carbon atoms and is preferablymethylene.

The compounds of formula I and their salts are known, or they can beprepared in a manner known per se.

For example, compounds of formula I wherein R₁ is hydrogen and R₂ isAr--S-- are obtainable by reaction of tetra-loweralkylmethane-diphosphonate with a disulfide of the formula Ar--S--S--Arin the presence of a strong metal base, such as NaH, and subsequent acidhydrolysis of the tetra-lower alkyl ester (see, for example, EP100,718).

Corresponding compounds of formula I wherein R₁ is hydrogen and R₂ isHet₁ --NH-- can be prepared, for example, by reacting a mixture of H₃PO₃ and PHal₃, wherein Hal is halogen, especially chlorine, with aformylamine of the formula Het₁ --NH--CHO or heating an amine Het₁ --NH₂with an orthoformic acid lower alkyl ester and a di-lower alkylphosphite, and hydrolysing the reaction product, for example in thepresence of an acid (see, for example, EP 274,346).

For the preparation of compounds of formula I wherein R₁ is hydrogen andR₂ is --A--R₃ and A is alkylene, it is possible, for example, to usecompounds of the formula R₃ --A--Hal as starting materials and to reactthose compounds with a tetra-lower alkylmethane-diphosphonate in thepresence of a strong base, for example NaH, and to hydrolyse theresulting tetra-lower alkyl ester of corresponding compounds of formulaI, for example in the presence of an acid, such as hydrochloric acid(see, for example, EP 275,821).

Compounds of formula I wherein R₁ is hydroxy and R₂ is --A--R₃ can beprepared, for example, by reacting a carboxylic acid of the formula R₂-COOH with a phosphorylating agent, such as a mixture of H₃ PO₃ andPHal₃, and working up under hydrolytic conditions (see, for example, EP170,228 and EP 252,505).

The methanediphosphonic acid derivatives of formula I have valuablepharmacological properties. In particular, they have a pronouncedregulatory effect on the calcium metabolism of warm-blooded animals.They also bring about a marked inhibition of bone resorption in rats,which can be demonstrated both in the test arrangement according to ActaEndocrinol. 78, 613-24 (1975) and in the TPTX(thyroparathyroidectomised) rat model by means of experimentalhypercalcaemia induced by vitamin D₃. Likewise, tumour hypercalcaemiainduced by Walker-256 tumours is inhibited following peroraladministration. Furthermore, in adjuvant arthritis in rats they exhibita pronounced inhibition of the progress of chronic-arthritic processesin the test arrangement according to Newbould, Brit. J. Pharmacology 21,127 (1963) and according to Kaibara et al., J. Exp. Med. 159, 1388-96(1984). They are therefore excellently suitable as active ingredients inmedicaments for the treatment of diseases that can be associated withdisorders of the calcium metabolism, for example inflammatory processesin joints and degenerative processes in articular cartilage, andosteoporosis, periodontitis, hyperparathyroidism and calcium deposits inblood vessels or on prosthetic implants. They have a favourable effectboth on diseases in which abnormal deposition of difficultly solublecalcium salts is observed, such as diseases of the arthritis type, forexample Bechterew's disease, neuritis, bursitis, periodontitis andtendinitis, fibrodysplasia, osteoarthritis or arteriosclerosis, and ondiseases involving abnormal degeneration of hard body tissue, such ashereditary hypophosphatasia, degenerative processes in articularcartilage, osteoporoses of various origins, Paget's disease andOsteodystrophia fibrosa, as well as osteolytic processes caused bytumours, and hypercalcaemia. Individual examples of the above-definedclass of substances are already being used therapeutically.

The invention relates especially to topically administrablepharmaceutical preparations that contain a pharmaceutically effectivemethanediphosphonic acid of formula I or a salt thereof, wherein each ofR₁ and R₂ is halogen, or wherein R₁ is hydrogen and R₂ is Ar--S--or Het₁--NH--, in which Ar is unsubstituted or substituted phenyl and Het₁ isunsubstituted or substituted, monocyclic, 5- or 6-membered monoaza-,diaza- or thiaza-aryl that is bonded via a ring carbon atom, or whereinR₁ is hydrogen or hydroxy and R₂ is --A--R₃, in which A is alkylene and,on the one hand, R₃ is Het₂, which is Het₁ bonded via a ring carbon orring nitrogen atom, or, on the other hand, R₃ is hydrogen, or amino thatis unsubstituted or mono- or di-substituted by identical or differentsubstituents selected from alkyl, Ar-alkyl, Ar-O-alkyl and Het₁ -alkyl,or that is di-substituted by optionally Ar-containing alkylene, whereintwo alkylene carbon atoms may additionally be linked to one another viaalkylene and Ar and Het₁ are each as defined above, with the provisothat when R₂ is --A--R₃, A is ethylene and R₃ is unsubstituted or C₁ -C₃alkyl-substituted amino, R₁ is other than hydroxy.

The invention relates especially to topically administrablepharmaceutical preparations that contain a pharmaceutically effectivemethanediphosphonic acid of formula I or a salt thereof, wherein each ofR₁ and R₂ is halogen, or wherein R₁ is hydrogen and R₂ is Ar--S-- orHet₁ --NH--, in which Ar is phenyl that is unsubstituted or substitutedby lower alkyl, lower alkoxy, trifluoromethyl and/or, especially, byhalogen, and Het₁ is unsubstituted or lower alkyl-substituted thiazolyl,or wherein R₁ is hydrogen or hydroxy and R₂ is --A--R₃, in which A islower alkylene and, on the one hand, R₃ is unsubstituted or loweralkyl-substituted imidazolyl that is bonded via a ring carbon or ringnitrogen atom, or is pyridyl, or, on the other hand, R₃ is hydrogen, oramino that is unsubstituted or mono- or di-substituted by identical ordifferent substituents selected from lower alkyl, C₃ -C₇ -cycloalkyl,Ar-lower alkyl, Ar--O-lower alkyl, Ar--S-lower alkyl and pyridyl-loweralkyl, or that is disubstituted by optionally Ar-containing loweralkylene or by lower alkylene wherein two non-adjacent lower alkylenecarbon atoms are additionally linked to one another via lower alkylene,and Ar in each case is as defined above, with the proviso that when R₂is --A--R₃, A is ethylene and R₃ is unsubstituted or C₁ -C₃alkyl-substituted amino, R₁ is other than hydroxy.

The invention relates preferably to topically administrablepharmaceutical preparations that contain a pharmaceutically effectivemethanediphosphonic acid of formula I or a salt, especially an alkalimetal salt, for example sodium salt, thereof, wherein each of R₁ and R₂is halogen, especially chlorine, or wherein R₁ is hydrogen and R₂ isphenylthio that is unsubstituted or substituted by halogen, such aschlorine, for example 4-chlorophenylthio, or thiazolylamino that isunsubstituted or substituted by lower alkyl, especially C₁ -C₄ alkyl,such as methyl, for example thiazol-2-yl-, 5-n-butylthiazol-2-yl-,5-ethylthiazol-2-yl- or 5-methylthiazol-2-yl-amino, or wherein R₁ ishydrogen or hydroxy and R₂ is --A--R₃ in which A is C₁ -C₇ alkylene,such as methylene, ethylene, propylene or pentylene, and R₃ isimidazolyl that is bonded via a ring carbon or ring nitrogen atom and isunsubstituted or substituted by lower alkyl, especially C₁ -C₄ alkyl,such as methyl, for example imidazol-1-yl, imidazol-5-yl,1-methylimidazol-2-yl or 4-methylimidazol-5-yl, or is pyridyl, such as2- or 3-pyridyl, or wherein R₁ is hydroxy and R₂ is --A--R₃ in which Ais as defined above and R₃ is amino, di-C₁ -C₅ alkylamino, such asdimethylamino, N-methyl-N-n-propylamino or N-methyl-N-n-pentylamino,N--C₃ -C₇ -cycloalkylamino, such as cycloheptylamino, N--C₁ -C₄alkyl-N-phenyl-C₁ -C₅ alkylamino, such asN-methyl-N-(2-phenylethyl)-amino, N-methyl-N-(3-phenylpropyl)-amino orN-methyl-N-(5-phenylpentyl)-amino, N--C₁ -C₄ alkyl-N-phenoxy-C₁ -C₄alkylamino, such as N-methyl-N-(3-phenoxypropyl)-amino, N--C₁ -C₄alkyl-N-phenylthio-C₁ -C₄ alkylamino, such asN-methyl-N-(2-phenylthioethyl)-amino, N--C₁ -C₄ alkyl-N-pyridyl-C₁ -C₄alkylamino, such as N-methyl-N-[3-(2-pyridyl)-propyl]-amino, C₄ -C₆alkyleneamino that is unsubstituted or substituted by phenyl which maycontain halogen, such as chlorine, such as 4-chlorophenyl, for examplepiperidin-1-yl that is unsubstituted or substituted, especially in the4-position, by phenyl, or pyrrolidin-1-yl that is unsubstituted orsubstituted, especially in the 3-position, by 4-chlorophenyl, or1,5-di-C₁ -C₄ alkyl-, such as 1,5-dimethyl-3-azabicyclo[3.1.1]hept-3-yl,or wherein R₁ is hydroxy and R₂ is --A--R₃ in which A is C₁ -C₄alkylene, especially methylene, and R₃ is hydrogen, with the provisothat when R₂ is --A--R₃, A is ethylene and R₃ is unsubstituted or C₁ -C₃alkyl-substituted amino, R₁ is other than hydroxy.

The invention relates especially to topically administrablepharmaceutical preparations that contain a pharmaceutically effectivemethanediphosphonic acid of formula I or a salt, especially an alkalimetal salt, for example sodium salt, thereof, wherein R₁ is hydroxy andR₂ is --A--R₃, in which A is C₂ -C₇ alkylene, such as ethylene,propylene or pentylene, and R₃ is amino, di-C₁ -C₄ alkylamino, such asdimethyl- or N-methyl-N-n-propyl-amino, N--C₃ -C₇ -cycloalkylamino, suchas cycloheptylamino, N--C₁ -C₄ alkyl-N-phenyl-C₁ -C₄ -alkylamino, suchas N-methyl-N-(3-phenylpropyl)-amino, N--C₁ -C₄ alkyl-N-phenoxy-C₁ -C₄alkylamino, such as N-methyl-N-(3-phenoxypropyl)-amino, or N--C₁ -C₄alkyl-N-phenylthio-C₁ -C₄ alkylamino, such asN-methyl-N-(2-phenylthioethyl)-amino, with the proviso that when R₂ is--A--R₃, A is ethylene and R₃ is unsubstituted or C₁ -C₃alkyl-substituted amino, R₁ is other than hydroxy.

The invention relates especially to topically administrablepharmaceutical preparations that contain a pharmaceutically effectivemethanediphosphonic acid of formula I or a salt, especially an alkalimetal salt, for example sodium salt, thereof, wherein R₁ is hydroxy andR₂ is --A--R₃, in which A is C₁ -C₇ alkylene, especially C₁ -C₄alkylene, such as methylene, and R₃ is imidazolyl that is bonded via aring carbon or ring nitrogen atom and is unsubstituted or substituted byC₁ -C₄ alkyl, such as methyl, such as especially imidazol-1-yl and alsoimidazol-5-yl, 1-methylimidazol-2-yl or 4-methylimidazol-5-yl.

The invention relates especially to topically administrablepharmaceutical preparations that contain a pharmaceutically effectivemethanediphosphonic acid selected from the following compounds offormula I:

4-amino-1-hydroxybutane-1,1-diphosphonic acid,6-amino-1-hydroxyhexane-1,1-diphosphonic acid,3-(N-methyl-N-n-pentylamino)-1-hydroxypropane-1,1-diphosphonic acid,3-[N-(3-phenylpropyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonicacid,3-(N-methyl-N-5-phenylpentylamino)-1-hydroxypropane-1,1-diphosphonicacid,3-[N-methyl-N-3-(2-pyridyl)-propylamino]-1-hydroxypropane-1,1-diphosphonicacid,1-hydroxy-3-[N-methyl-N-(3-phenoxypropyl)-amino]-propane-1,1-diphosphonicacid,1-hydroxy-3-[N-methyl-N-(2-phenoxyethyl)-amino]-propane-1,1-diphosphonicacid, 4-(4-phenyl-piperidin-1-yl)-1-hydroxybutane-1,1-diphosphonic acid,1-hydroxy-3-(1-piperidino)-propane-1,1-diphosphonic acid,1-hydroxy-3-[3-(4-chlorophenyl)-pyrrolidin-1-yl]-propane-1,1-diphosphonicacid, 1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid,2-(1-methylimidazol-2-yl)ethane-1,1-diphosphonic acid,1-hydroxy-2-(4-methylimidazol-5-yl)-ethane-1,1-diphosphonic acid,1-hydroxy-2-(imidazol-5-yl)-ethane-1,1-diphosphonic acid,1-hydroxy-2-(3-pyridyl)-ethane-1,1-diphosphonic acid,2-(2-pyridyl)-ethane-1,1-diphosphonic acid,1-[(5-n-butyl-2-thiazolyl)-amino]-methane-1,1-diphosphonic acid,1-[(5-methyl-2-thiazolyl)-amino]-methane-1,1-diphosphonic acid,1-[(2-thiazolyl)-amino]-methane-1,1-diphosphonic acid,1-hydroxyethane-1,1-diphosphonic acid,1-(4-chlorophenylthio)methane-1,1-diphosphonic acid,1,1-dichloromethane-1,1-diphosphonic acid or3-(1,5-dimethyl-3-azabicyclo[3.1.1]hept-3-yl)-1-hydroxypropane-1,1-diphosphonicacid, and also 1-[(5-ethyl-2-thiazolyl)-amino]-methane-1,1-diphosphonicacid,3-[N-(2-phenylethyl)N-methylamino]-1-hydroxypropane-1,1-diphosphonicacid,3-[N-(2-phenylthioethyl)N-methylamino]-1-hydroxypropane-1,1-diphosphonicacid, 1-hydroxy-3-(pyrrolidin-1-yl)-propane-1,1-diphosphonic acid or2-(N-cycloheptylamino)-ethane-1,1-diphosphonic acid, or apharmaceutically acceptable salt thereof.

The invention relates also to a process for the manufacture of thetopically administrable pharmaceutical preparations according to theinvention, which process may be carried out in accordance with methodsknown per se and comprises processing a pharmaceutically acceptablemethane diphosphonate derivative with customary pharmaceuticallyacceptable adjuncts and additives.

The invention relates further to a method of increasing the absorptionof pharmaceutically acceptable methanediphosphonic acid derivatives,especially of compounds of formula I, which comprises incorporating acompound of formula I or a salt thereof into a pharmaceuticalcomposition for topical administration.

The invention relates specifically to the pharmaceutical preparationsdescribed in the examples and to processes for the manufacture thereof.

Depending on the starting materials and procedures chosen, the compoundsof formula I may be in the form of one of the possible isomers or in theform of a mixture thereof, for example in the form of optical isomers,such as enantiomers or diastereoisomers, or geometrical isomers, such ascis-trans isomers. The optical isomers are in the form of the pureantipodes and/or of racemates.

The compounds of formula I may also be employed in the form of theirhydrates or include other solvents used for crystallisation.

The topically administrable pharmaceutical preparations according to theinvention contain the pharmaceutically acceptable compounds of formulaI, for example, in a pharmacologically effective amount, together with apharmaceutically acceptable additive or adjunct. The daily dose ofactive ingredient depends on age and individual condition and on themethod of administration.

Pharmaceutical preparations suitable for topical administration areespecially creams, ointments and gels and also pastes, foams, tincturesand solutions that contain from approximately 0.5 to approximately 5%active ingredient.

Creams or lotions are oil-in-water emulsions that contain more than 50%water. As oily base there are used especially fatty alcohols, especiallythose containing from 12 to 18 carbon atoms, for example lauryl, cetylor stearyl alcohol, fatty acids, especially those containing from 10 to18 carbon atoms, for example palmitic or stearic acid, liquid to solidwaxes, for example isopropyl myristate, wool wax or beeswax, and/orhydrocarbons, especially liquid, semi-solid or solid substances ormixtures thereof, for example petroleum jelly (petrolatum) or paraffinoil. Suitable emulsifiers are surface-active substances havingpredominantly hydrophilic properties, such as corresponding non-ionicemulsifiers, for example fatty acid esters of polyalcohols or ethyleneoxide adducts thereof, especially corresponding fatty acid esters with(poly)ethylene glycol, (poly)propylene glycol or sorbitol, the fattyacid moiety containing especially from 10 to 18 carbon atoms, especiallypartial glycerol fatty acid esters or partial fatty acid esters ofpolyhydroxyethylene sorbitan, such as polyglycerol fatty acid esters orpolyoxyethylene sorbitan fatty acid esters (Tweens), and alsopolyoxyethylene fatty alcohol ethers or fatty acid esters, the fattyalcohol moiety containing especially from 12 to 18 carbon atoms and thefatty acid moiety especially from 10 to 18 carbon atoms, especiallythose having approximately from 2 to 23 ethylene glycol or ethyleneoxide units, such as polyhydroxyethylenecetylstearyl ether (for exampleCetomacrogol), polyhydroxyethylene-(4)-lauryl ether andpolyhydroxyethyleneglycerol fatty acid ester (for example Tagat S), orcorresponding ionic emulsifiers, such as alkali metal salts of fattyalcohol sulfates, especially having from 12 to 18 carbon atoms in thefatty alcohol moiety, for example sodium lauryl sulfate, sodium cetylsulfate or sodium stearyl sulfate, which are usually used in thepresence of fatty alcohols, for example cetyl alcohol or stearylalcohol. Additives to the aqueous phase are, inter alia, agents thatprevent the creams from drying out, for example humectants, such aspolyalcohols, such as glycerol, sorbitol, propylene glycol and/orpolyethylene glycols, and also preservatives, perfumes, etc.

Ointments or lotions are water-in-oil emulsions that contain up to 70%,but preferably from approximately 20% to approximately 50%, water oraqueous phase. Suitable as fatty phase are especially hydrocarbons, forexample petroleum jelly, paraffin oil and/or hard paraffins, which, inorder to improve the water-binding capacity, preferably contain suitablehydroxy compounds, such as fatty alcohols or esters thereof, for examplecetyl alcohol or wool wax alcohols, or wool wax. Emulsifiers arecorresponding lipophilic substances, for example of the type indicatedabove, such as sorbitan fatty acid esters (Spans), for example sorbitanoleate and/or sorbitan isostearate. Additives to the aqueous phase are,inter alia, humectants, such as polyalcohols, for example glycerol,propylene glycol, sorbitol and/or polyethylene glycol, and alsopreservatives, perfumes, etc.

Microemulsions are isotropic systems based on the following fourcomponents: water, an emulsifier, for example of the type indicatedabove, such as a surfactant, for example emulgin, a lipid, such as anon-polar oil, for example paraffin oil, and an alcohol containing alipophilic group, for example 2-octyldodecanol. If desired, otheradditives may be added to the microemulsions.

Fatty ointments are water-free and contain as base especiallyhydrocarbons, for example paraffin, petroleum jelly and/or liquidparaffins, also natural or partially synthetic fat, such as fatty acidesters of glycerol, for example coconut fatty acid triglyceride, orpreferably hardened oils, for example hydrogenated groundnut oil orcastor oil, also fatty acid partial esters of glycerol, for exampleglycerol mono- and di-stearate, and also, for example, the fattyalcohols increasing the water-absorption capacity, emulsifiers and/oradditives mentioned in connection with the ointments.

With gels, a distinction is made between aqueous gels, water-free gelsand gels having a low water content, which gels consist of swellable,gel-forming materials. There are used especially transparent hydrogelsbased on inorganic or organic macromolecules. High molecular weightinorganic components having gel-forming properties are predominantlywater-containing silicates, such as aluminium silicates, for examplebentonite, magnesium aluminium silicates, for example Veegum, orcolloidal silicic acid, for example Aerosil. As high molecular weightorganic substances there are used, for example, natural, semi-syntheticor synthetic macromolecules. Natural and semi-synthetic polymers arederived, for example, from polysaccharides containing a great variety ofcarbohydrate components, such as celluloses, starches, tragacanth, gumarabic and agar-agar, and gelatin, alginic acid and salts thereof, forexample sodium alginate, and derivatives thereof, such as loweralkylcelluloses, for example methyl- or ethyl-cellulose, carboxy- orhydroxy-lower alkylcelluloses, for example carboxymethyl- orhydroxyethyl-cellulose. The components of synthetic gel-formingmacromolecules are, for example, suitably substituted unsaturatedaliphatic compounds such as vinyl alcohol, vinylpyrrolidine, acrylic ormethacrylic acid. Examples of such polymers are polyvinyl alcoholderivatives, such as polyviol, polyvinylpyrrolidines, such as collidone,polyacrylates and polymethacrylates, especially having a molecularweight of from approximately 80000 to approximately 1 million, or saltsthereof, such as Rohagit S, Eudispert or Carbopol. Customary additives,such as preservatives or perfumes, may be added to the gels.

Foams are administered, for example, from pressurised containers and areliquid oil-in-water emulsions in aerosol form; unsubstituted orhalogenated hydrocarbons, such as alkanes, for example propane orbutane, or chlorofluoro-lower alkanes, for exampledichlorodifluoromethane and dichlorotetrafluoroethane, are used aspropellant. As oil phase there are used, inter alia, hydrocarbons, forexample paraffin oil, fatty alcohols, for example cetyl alcohol, fattyacid esters, for example isopropyl myristate, and/or other waxes. Asemulsifiers there are used, inter alia, mixtures of emulsifiers havingpredominantly hydrophilic properties, such as polyoxyethylene sorbitanfatty acid esters (Tweens), and emulsifiers having predominantlylipophilic properties, such as sorbitan fatty acid esters (Spans). Thecustomary additives, such as preservatives, etc., are also added.

Tinctures and solution generally have an ethanolic base, to which watermay be added and to which there are added, inter alia, polyalcohols, forexample glycerol, glycols and/or polyethylene glycol, as humectants forreducing evaporation, and fat-restoring substances, such as fatty acidesters with low molecular weight polyethylene glycols, that is to saylipophilic substances that are soluble in the aqueous mixture, as areplacement for the fatty substances removed from the skin by theethanol, and, if necessary, other adjuncts and additives. Suitabletinctures or solutions may also be applied in spray form by means ofsuitable devices.

The manufacture of the topically administrable pharmaceuticalpreparations is effected in a manner known per se, for example bydissolving or suspending the active ingredient in the base or, ifnecessary, in a portion thereof. When the active ingredient isadministered in the form of a solution, it is generally dissolved in oneof the two phases before emulsification; when the active ingredient isadministered in the form of a suspension, it is mixed with a portion ofthe base after emulsification and then added to the remainder of theformulation.

The present invention relates especially to multi-layered therapeuticsystems for the transdermal administration of pharmaceuticallyacceptable methanediphosphonic acid derivatives, especially those offormula I, and their salts, which contain essentially the followingconstituents:

(1) a closed backing foil which is impermeable to the subsequent layersof the constituents of the active ingredient formulation,

(2) a reservoir for the active ingredient, next to the backing foil,provided that the active ingredient is not already present in theadhesive foil,

(3) an adhesive layer and

(4) a peel-off protecting foil.

The therapeutic system according to the invention for the transdermaladministration of methanediphosphonic acid derivatives of formula I ispreferably in the form of a plaster having a base surface that is atleast as large in area as the area of the skin envisaged for theadministration and at least as large as is required for it to stayfirmly in place over the entire period of treatment. The base surfacemust be large enough for sufficient quantities of the activeconstituents of the active ingredient formulation (for example, activeingredient and the agents for enhancing percutaneous absorption,hereinafter "penetration enhancers") to be absorbed by the skin.Although, in theory, very large areas of skin are available for takingthe plaster, for reasons of comfort the wanted surface area of the basesurface of the plaster is about 200 cm², in the first line about 20 toabout 30 cm².

The plaster may be of any geometrical shape, e.g. may be oval,elliptical, circular, rectangular, optionally with rounded corners,oblong or rectangular with one or two rounded tabs. Other shapes arealso possible.

The backing foil (1) consists of a material or of a combination ofmaterials that must be impermeable to the constituents of theformulation contained in the reservoir (2). It serves as a protectingand carrier layer. To produce the backing foil, it is possible to usehigh or low pressure polymers such as polyethylene, polypropylene,polyvinyl chloride, polyurethane, polyethylene terephthalate or alsocellulose acetate or vinyl acetate/vinyl chloride copolymers andcombinations, especially composite foils thereof. An impermeable,flexible backing foil that conforms to the shape of the part of the bodyto which the plaster is applied and that consists of materials suitablefor the manufacture of hot form-sealed systems is preferred.

The reservoir (2) for the active ingredient is situated between thebacking foil (1) and the adhesive layer (3), which in turn is arrangedon the peel-off protecting foil (4), and contains all essentialconstituents of the active ingredient formulation. The reservoir servesto hold the active ingredient in a limited space for release to theskin. It may contain a liquid, semi-solid or solid active ingredientformulation or may formed as homogeneous or inhomogeneous polymer matrixcontaining itself the active ingredients. Preferably, the reservoirlayer containing the active ingredient is formed as adhesive matrixwhich in case of a monolith system needs no additional adhesive layer.In an other preferred embodiment as reservoir a liquid or semi-solidcomposition which contains the active ingredient and which may melt askin temperature is embedded in a non-woven fabric or in a polymericfoam.

However, if the reservoir is not itself the adhesive matrix or isincorporated in an adhesive layer, it can be bonded to an adhesivelayer, which in turn can be bonded to the peel-off layer. Furthermore, aporous or permeable membrane may be arranged between the reservoir andan adhesive layer which in turn is arranged on a peel-off layer (4).

For example, an arrangement in which the reservoir is in firm contactwith the skin is known per se and is described, for example, in BritishPatent Application 2,021,950. The area of the backing foil (1) isgreater than the area occupied by the reservoir (2) and, therefore, thebacking foil projects beyond the reservoir, the projecting portion ofthe backing foil (1) being provided with an adhesive layer and adheringto the skin. The peel-off protecting foil (4) lies over the adhesivelayer (3) and over the reservoir (2), it being possible for the latteralso to be limited by an additional membrane.

An example of a system in which the reservoir (2) is, for example, infirm contact with the adhesive layer (3), it being possible for theactive ingredient base to be present both in the reservoir and in theadhesive layer, is described in U.S. Pat. No. 4,597,961. The backingfoil (1) is also larger in area than the area occupied by the reservoir(2) and projects beyond the latter. The adhesive layer (3) covers boththe reservoir (2) and the projecting portion of the backing foil (1).The peel-off protecting foil (4) lies on top of the adhesive layer.

The matrix used for immobilising drug compositions which are liquid orsemi-solid or which melt at skin temperature essentially consists of,for example, natural or synthetic polymers, such as cotton, cellulose,regenerated cellulose, polyamides, polyester, polyurethane or cellulosederivatives, for example those of the type described below, viscose orpolypropylene. In particular, such fibrous structures are used in theform of a non-woven fabric or in form of woven and mitted fabrics andalso foams.

The reservoir (2) can also contain liquid polymeric material in whichthe active ingredient formulation or constituents thereof arehomogeneously dispersed. Such polymeric materials are, for example,silicone rubber (silicones), e.g. linear organosiloxanes in which everysilicon atom in the siloxane chain is substituted by two identical ordifferent alkyl, e.g. methyl or ethyl, aryl, e.g. phenyl, alkenyl, e.g.vinyl or allyl, alkylaryl, e.g. tolyl or xylyl, or aralkyl, e.g. benzyl,radicals, and every terminal silicon atom is substituted by three of thementioned organic radicals. The preparation of these silicones isdescribed in U.S. Pat. Nos. 2,541,137, 2,723,966, 2,863,846, 2,890,188,2,927,907, 3,002,951 and 3,035,016.

In addition to the liquid polymeric material and the active ingredientformulation, the reservoir (2) can also contain other liquids such asglycerol or propylene glycol and also water and have the releaseproperties described in U.S. Pat. No. 4,291,015.

The contents of the reservoir (2) preferably consist exclusively of theactual active ingredient formulation which contains the penetrationenhancer, especially ethanol, the active ingredient and, optionally,other auxiliaries, for example gelling agents and, optionally,viscosity-increasing adjuncts, such as polyvinyl alcohol,polyvinylpyrrolidone, cellulose derivatives, e.g. those of the typementioned, and gelatin.

The reservoir (2) can, in addition, be provided with a permeable layerof the required permeability to the active ingredient and thepenetration enhancer. This layer controls the rate of release of thepenetration enhancer and/or of the active ingredient from the system tothe skin and is also called a control or regulating membrane.

The materials that can be used in the therapeutic systems of theinvention for producing the permeable layer are known per se. Suchmembrane materials may be homogeneous (diffusion membranes) ormacrostructured (porous membranes). The latter may be regarded as beinga sponge-like structure having a skeleton of polymeric material withinterconnected voids and pores dispersed therein. Membrane materialsthat control the rate of release may consist of isotropic material witha homogeneous structure or of anisotropic material with anon-homogeneous structure. Such materials are commercially available andcan be produced in various ways, for example as described by R. E.Kesting, Synthetic Polymer Membranes, McGraw Hill, Chapters 4 and 5,1971, J. D. Ferry, Ultrafiltration Membranes, Chemical Review, Vol. 18,page 373, 1984.

Membrane materials having from 5 to 95% by volume voids and an effectivepore diameter of approximately from 1.0×10⁻⁹ m to 1.0×10⁻⁴ m areespecially suitable. More especially suitable are membrane materialshaving pore diameters of less than approximately 5.0×10⁻⁹ m andmolecular diffusion. For best results, reference should be made to theprior art and the known embodiments with known membrane materials andknown shapes which ensure an optimum rate of release of the activeingredient. In particular, the membrane material must be chemicallyresistant to the active ingredient and to the penetration enhancer used.

A list of suitable membrane materials, which should not be regarded asexhaustive, is given below:

polycarbonates, e.g. linear polyesters of carbonic acid derivatives thatcontain carbonate groups in the polymer chain and can be prepared, forexample, by reacting dihydroxy aromatic compounds with phosgene. Suchmaterials are obtainable from General Electric under the trade markLexan®;

polyvinyl chlorides, e.g. PVC, which is obtainable from Goodrich underthe trade mark Geon® 121;

polyamides of the polyhexamethyleneadipamide type, or polyamides knownby the generic name "Nylon". An especially suitable material is soldunder the trade mark Nomex® by DuPont;

acrylic acid copolymers, e.g. those which are sold under the trade nameDynel® and consist of about 60% polyvinyl chloride and 40%acrylonitrile, and styrene/acrylic acid copolymers and the like;

polysulfones with diphenylsulfone groups in the linear chain. Suchpolymers are sold as P-1700 by Union Carbide;

halogenated polymers, such as polyvinylidene fluorides, that are sold,for example, under the trade mark Kynar® by Pennwalt; polyvinylfluorides that are obtainable from DuPont under the trade mark Tedlar®,and polyfluorohalocarbons obtainable under the trade mark Aclar® fromAllied Chemical;

polychloroethers that are sold by Hercules under the trade mark Penton®,and other similar thermoplastic polymers;

acetal polymers such as the polyformaldehyde polymers that are sold byDuPont under the trade mark Delrin®, and the like;

acrylic acid resinates, such as polymethyl methacrylate, poly-n-butylmethacrylate and the like;

polyethylene and copolymers of ethylene, e.g. with vinyl acetate oracrylates.

other polymers, such as polyurethanes, polyimides, polybenzimidazoles,polyvinyl acetate, aromatic and aliphatic polyethers, cellulose esters,for example cellulose triacetate, cellulose, Colledion® (cellulosenitrate with 11% nitrogen), epoxy resinates, polyolefins, e.g.polyethylene/polypropylene, porous rubber, polyvinylpolypyrrolidone,crosslinked polyvinyl alcohol, copolymers of vinylpyrrolidone and vinylalcohols, polyelectrolyte structures consisting of two ionicallyassociated polymers as are described in U.S. Pat. Nos. 3,549,016 and3,546,142, polystyrene derivatives such as polystyrene sodium sulfonatesor polyvinylbenzyltrimethylammonium chlorides, polyhydroxyethylmethacrylates, polyisobutyl vinyl ether and similar polymers can also beused. Other copolymers that are obtainable by copolymerisation ofvarious amounts of the monomers forming the basis of the mentionedpolymers can also be used to produce the membrane material determiningthe rate of release of the active ingredient and/or the penetrationenhancer.

When using a permeable membrane, several arrangements are possible: theactive ingredient formulation is arranged between the backing foil (1)and the membrane. In that arrangement, the backing foil and the membraneform a space which can optionally be divided into several compartments.In certain embodiments, the backing foil (1) and the membrane arejoined, e.g. welded or glued, to each other at the very edge. In theseembodiments, the active ingredient and the penetration enhancer arecontained in the same reservoir. These embodiments are preferred whenthe active ingredient formulation is liquid or semi-solid.

It is also possible, in accordance with the embodiment described inGerman Offenlegungsschrift 3,205,258, to fill the space formed by thebacking foil (1) and the membrane only with penetration enhancer, e.g.ethanol, and optionally with a gelling agent or viscosity-increasingadjunct, such as gelatin, and to apply the active ingredient formulationto the other side of the membrane. In that case, the membrane wouldcontrol only the rate of diffusion of the enhancer. The activeingredient can be present in a separate layer between membrane andadhesive layer (3) and optionally or exclusively in the adhesive layer(3).

The reservoir (2) can, in addition, be divided into severalcompartments. This division into compartments is suitable for liquidactive ingredient formulations and prevents the latter from sinking andbecoming concentrated at the lowest point of the system if cavities orfolds are formed as a result of the plaster not being stored flat.Division into compartments is especially advantageous if the reservoirlayer occupies an area of more than 30 cm². The compartments can bedistributed as desired. For example, a radial arrangement of thepartitions, extending from the middle point of the plaster, or verticalor horizontal boundaries, or oblique lines etc. are possible.

Division of the compartments, especially by partitions or seal seams,can be effected by hot-welding. In this procedure, the material of thebacking foil (1) is welded to the material of the membrane layer.

Dermatologically acceptable adhesives are suitable for the adhesivelayer (3). Suitable adhesives are, for example, silicone adhesives [e.g.of the Bio-PSA® or Silicon Adhesive 355 (Dow Corning) type], adhesiveformulations of acrylic acid resins or methacrylic acid resins, e.g.polymers of acrylic acid or methacrylic acid esterified by alcohols suchas n-butanol, n-pentanol, isopentanol, 2-methylbutanol, 1-methylbutanol,1-, 2- or 3-methylpentanol, 2-ethylbutanol, isooctanol, n-decanol orn-dodecanol, or copolymers of these acrylic acid or methacrylic acidesters with monomers containing ethylene groups, such as acrylic aciditself, methacrylic acid, acrylamide, methacrylamide,N-alkoxymethacrylamide, N-alkoxymethylmethacrylamide,N-tert.-butylamide, itaconic acid, vinyl acetate [e.g. of the Durotak®280-2516 type (National Starch & Chemical B.V.)], N-branched alkylmaleicacid amide in which the branched alkyl group has from 10 to 24 carbonatoms, glycol diacrylates or mixtures thereof, polyalkenylenes, such aspolyisobutylenes of different molecular weights, for example of fromapporoximately 100 to 1.5 million, e.g. polyisobutylene 300 or 35000 or1.2 million, hydrogenated hydrocarbon resins, natural or syntheticrubber, such as styrenebutadiene, butyl ether, neoprene,polyisobutylene, polybutadiene and polyisoprene, polyvinyl acetate,urea/formaldehyde resinates, resorcinol/formaldehyde resinates,cellulose derivatives such as ethylcellulose, methylcellulose,nitrocellulose, cellulose acetate butyrate and carboxymethylcellulose,and also natural gums such as agar, acacia, pectin, starch, dextrin,albumin, gelatin, casein, etc. Also suitable as adhesives arecorresponding silicone adhesives. It is also possible to add thickenersand stabilisers and also solvents to the mentioned adhesives; however,they may be used without solvents in the form of so-called hot-meltadhesives, which are applied at higher temperatures to the polymericmaterials in the molten state. The solvents in which the adhesives aredissolved are, especially, are readily volatile and tolerated by theskin. Examples that may be mentioned are corresponding hydrocarbons,such as alkanes, e.g. hexane, heptane, aromatic hydrocarbons, e.g.toluene, lower alkanols, such as methanol, ethanol or isopropanol,esters, such as lower alkanecarboxylic acid-lower alkyl esters, e.g.ethyl acetate, or ketones, such as acetyl acetone, or mixtures thereof.

The adhesive layer (3) may be applied to some or all of the membrane. Ifthe membrane is completely covered by the adhesive layer, the lattermay, in addition to its actual function as an adhesive to the skin, actas a permeable membrane. The desired membrane properties, e.g. controlof the rate of diffusion of the penetration enhancer, can be obtained byvarying the thickness and composition of the adhesive layer (3). Theadhesive layer (3) may, in addition, contain the total amount or,preferably, a portion of the active ingredient. The amount of activeingredient contained in the adhesive layer (3) can be used, inparticular, to administer an initial surge dose before the continuousrelease, which is controlled by the therapeutic system, commences at thedesired therapeutic level.

The membrane can also be covered by the adhesive layer (3) partiallyand/or discontinuously. A covering at the edges is possible, for examplean annular circumferential covering. The membrane can also be covered ina pattern, for example in a rhomboidal pattern. The membrane can becovered at the outer edge by a continuous band of adhesive material, forexample in the shape of a ring, and on the inside surface withdiscontinuous bands, for example in a rhomboidal pattern.

The protecting foil (4) is removed before application. It consists ofmaterials that are impermeable to the constituents of the reservoirlayer (2). It is possible to use the same materials as those used forproducing the backing foil (1), and also metal foils, for example thinaluminium foil. Organic polymers are rendered capable of being peeledoff the adhesive layer, for example, by suitable surface treatment, forexample silicone treatment.

The active ingredient formulation contained in the transdermaltherapeutic system of the invention, especially in the reservoir (2),contains as adjunct an agent that enhances percutaneous absorption(penetration enhancer--"flux enhancer") which increases the flux of theactive ingredients of formula I through the skin, so that a greaterquantity of active ingredients is absorbed by the skin per unit ofapplication area and per unit of time. The penetration enhancer can, inaddition, accelerate the flow of the active ingredient through thepermeable membrane layer in membrane systems. In particular, the use ofa suitable penetration enhancer results in the administration throughthe skin of that dosage of active ingredients which is required per unitof time to maintain the therapeutic level. Penetration enhancers canenhance the permeability of the skin without permanently harm the skinto the active ingredient and can be mixed with other pharmaceuticallyacceptable adjuncts.

Suitable penetration enhancers are preferably monovalent, saturated orunsaturated aliphatic, cycloaliphatic or aromatic alcohols having from 4to 12 carbon atoms, e.g. n-hexanol or cyclohexanol, aliphatic,cycloaliphatic or aromatic hydrocarbons having from 5 to 12 carbonatoms, e.g. hexane, cyclohexane, isopropylbenzene and the like,cycloaliphatic or aromatic aldehydes and ketones having from 4 to 10carbon atoms, such as cyclohexanone, acetamide, N,N-di-loweralkylacetamides such as N,N-dimethylacetamide or N,N-diethylacetamide,C₁₀ -C₂₀ alkanoylamides, e.g. N,N-dimethyllauroylamide, 1-n-C₁₀ -C₂₀alkylazacycloheptan-2-one, e.g. 1-n-dodecylazacycloheptan-2-one (Azone®,Nelson), pyrrolidones, such as N-methylpyrrolidone, polyalkylene glycollaureates, e.g. polyethylene glycol monolaureate orN-2-hydroxyethylacetamide, and known vehicles and/or penetrationenhancers such as aliphatic, cycloaliphatic and aromatic esters,N,N-di-lower alkyl sulfoxide, unsaturated oils, halogenated or nitratedaliphatic or cycloaliphatic hydrocarbons, salicylates, polyalkyleneglycol silicates, and mixtures thereof.

C₂ -C₄ alkanols, e.g. isopropanol or isobutanol and, especially,ethanol, are especially preferred as penetration enhancers.

The amount of active ingredient, present in the therapeutic system, thatis required to achieve a therapeutic effect depends on many factors:inter alia the minimum necessary dosage, the permeability of themembrane material, which determines the flux, and of the adhesive layer,and the period for which the plaster will be fixed to the skin or themucous membranes. Since the active ingredient is to be released over aperiod of more than one day, there is, in fact, no upper limit to themaximum amounts of active ingredient present in the plaster. The minimumamount of active ingredient is determined by the requirement thatsufficient, for example therapeutically effective, quantities of activeingredient must be present in the plaster to maintain the desired rateof release over the given period.

Adjuncts can be added to the active ingredients. Suitable adjuncts arewater, isotonic aqueous sodium chloride solution, dextrose in water orsodium chloride solution, liquid glyceryl triesters with low molecularweight fatty acids, lower alkanols, natural oils such as corn oil,groundnut oil, sesame oil, castor oil and condensation products thereofwith ethylene oxide, and the like, hydrocarbons such as pharmaceuticalgrade mineral oil, silicones, emulsifiers such as monoglycerides ordiglycerides of fatty acids, phospholipic acid derivatives such aslecithin or cephalin, polyalkylene glycols such as polyethylene glycol,aqueous phases to which a swelling agent such as sodiumcarboxymethylcellulose, sodium alginate, polyvinylpolypyrrolidone, etc.has been added and to which, in addition, dispersion agents oremulsifiers such as lecithin may be added, polyoxyethylene and the like.The adjuncts may, in addition, contain additives such as preservatives,stabilisers, wetting agents, emulsifiers, etc.

If C₂ -C₄ alkanols such as ethanol are used as penetration enhancers,gelling agents such as gelatin or swelling agents such as celluloseethers, e.g. hydroxypropylcellulose, are preferably added as adjuncts tothe active ingredient formulation.

The transdermal therapeutic systems of the invention are prepared in amanner known per se, for example as follows: the adhesive layer (3) isapplied to a base layer (peel-off protecting foil (4)), e.g. foil orfilm. The constituents of the active ingredient reservoir, for examplemembrane layer and active ingredient formulation, can also be applied tothe base layer, and the impermeable backing foil can be placed on top.The plaster is then punched out of the master. The reservoir isoptionally bonded to the backing foil with additional adhesive. Thereservoir can also be hot-welded to the membrane layer or to theadhesive layer. In liquid-filled systems, the membrane layer is appliedto the adhesive layer and the active ingredient formulation is placed onthe membrane.

The preparation processes are described in U.S. Pat. No. 3,797,494,preferably in DE-A-26 04 718 and DE-A-32 05 258 and in U.S. Pat. Nos.4,031,894 and 4,262,003 or in the publication by H. Asche in Schweiz.Rundschau Med. (Praxis) 74, No. 11, 257-260 (1985), but the useaccording to the invention is not limited to the transdermal therapeuticsystems described in those publications. The preferred transdermaltherapeutic system described in DE-A 32 05 258 is a therapeutic systemin the form of a plaster-like patch that releases the active ingredienttransdermally, avoiding side-effects, and delivers it through the skinso that the active ingredient content of the plasma remainsapproximately constant.

The daily dose of active ingredient for a patient weighing about 70 kgis estimated to be from approximately 50 μg to approximately 150 μg,depending on the potency of the particular active ingredient used. Thefollowing Examples illustrate the invention described above, but they donot limit the scope thereof in any way.

EXAMPLE 1

Gel, containing as active ingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid, having thefollowing composition:

    ______________________________________                                        active ingredient 1.0 g                                                       Carbopol 934 P    1.0 g                                                       glycerol          3.0 g                                                       isopropanol       25.0 g                                                      Softigen 767      0.2 g                                                       demin. water q.s. ad                                                                            100.0 g                                                     ______________________________________                                    

EXAMPLE 2

Solution, containing as active ingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid, having thefollowing composition:

    ______________________________________                                        active ingredient 1.0 g                                                       isopropanol       60.0 g                                                      propylene glycol  10.0 g                                                      demin. water q.s. ad                                                                            100.0 g                                                     ______________________________________                                    

EXAMPLE 3

Microemulsion, containing as active ingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid, having thefollowing composition:

    ______________________________________                                        active ingredient 1.0 g                                                       Labrasol*         32.9 g                                                      Plurolisostearate**                                                                             13.2 g                                                      isostearyl isostearate                                                                          41.9 g                                                      demin. water q.s. ad                                                                            100.0 g                                                     ______________________________________                                         *glyceryl caprylate/caprate (and) PEG8                                        **polyglycerol6-isostearate                                              

EXAMPLE 4

Cream (W/O), containing as active ingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid, having thefollowing composition:

    ______________________________________                                        active ingredient      1.0    g                                               cetyl alcohol          6.5    g                                               cetyl palmitate        5.0    g                                               stearyl alcohol        6.5    g                                               petroleum jelly        5.0    g                                               glycerol               12.5   g                                               sodium laurylsulfate   1.0    g                                               methylparaben          0.18   g                                               propylparaben          0.05   g                                               demin. water q.s. ad   100.0  g                                               ______________________________________                                    

EXAMPLE 5

Ointment (O/W emulsion), containing as active ingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid, having thefollowing composition:

    ______________________________________                                        active ingredient      1.0    g                                               cetyl alcohol          3.0    g                                               glycerol               6.0    g                                               methylparaben          0.18   g                                               propylparaben          0.05   g                                               Arlacel 60             0.6    g                                               Tween 60               4.4    g                                               stearic acid           9.0    g                                               isopropyl palmitate    2.0    g                                               paraffin oil, viscous  10.0   g                                               demin. water q.s. ad   100.0  g                                               ______________________________________                                    

EXAMPLE 6

Water-free ointment, containing as active ingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid, having thefollowing composition:

    ______________________________________                                        active ingredient 1.0 g                                                       petroleum jelly   35.0 g                                                      paraffin oil, viscous                                                                           35.0 g                                                      Lanette N         30.0 g                                                      ______________________________________                                    

EXAMPLE 7

Lotion, containing as active ingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid, having thefollowing composition:

    ______________________________________                                        active ingredient      1.0    g                                               cetyl alcohol          1.9    g                                               glycerol               4.3    g                                               sodium laurylsulfate   1.0    g                                               methylparaben          0.18   g                                               propylparaben          0.05   g                                               paraffin oil, viscous  2.5    g                                               demin. water q.s. ad   100.0  g                                               ______________________________________                                    

EXAMPLE 8

Foam, containing as active ingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid, having thefollowing composition:

    ______________________________________                                        active ingredient      1.0    g                                               cetyl alcohol          1.7    g                                               glycerol               5.0    g                                               methylparaben          0.18   g                                               propylparaben          0.05   g                                               isopropyl palmitate    2.0    g                                               Arlacel 83             1.5    g                                               Cetomacrogol 1000      2.4    g                                               paraffin oil, viscous  1.0    g                                               demin. water q.s. ad   100.0  g                                               ______________________________________                                    

EXAMPLE 9

Monolith adhesive transdermal system, containing as active ingredient,for example, 1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acidComposition:

    ______________________________________                                        polyisobutylene (PIB) 300                                                                           5.0 g                                                   (Oppanol B1, BASF)                                                            PIB 35000             3.0 g                                                   (Oppanol B10, BASF)                                                           PIB 1200000           9.0 g                                                   (Oppanol B100, BASF)                                                          hydrogenated hydrocarbon resin                                                                      43.0 g                                                  (Escorez 5320, Exxon)                                                         1-dodecylazacycloheptan-2-one                                                                       20.0 g                                                  (Azone, Nelson Res., Irvine/CA)                                               active ingredient     20.0 g                                                  Total                 100.0 g                                                 ______________________________________                                    

PREPARATION

The above components are together dissolved in 150 g of special boilingpoint petroleum fraction 100-125 by rolling on a roller gear bed. Thesolution is applied to a polyester film (Hostaphan, Kalle) by means of aspreading device using a 300 μm doctor blade, giving a coating of about75 g/m². After drying (15 minutes at 60° C.), a silicone-treatedpolyester film (thickness 75 μm, Laufenberg) is applied as the peel-offfilm. The finished systems are punched out in sizes in the wanted formof from 5 to 30 cm² using a punching tool. The complete systems aresealed individually in sachets of aluminised paper.

EXAMPLE 10

Matrix transdermal system with adhesive coating at the edge only,containing as active ingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid Composition:

    ______________________________________                                        active ingredient     10.0 g                                                  hydroxypropylcellulose                                                                              1.0 g                                                   (Klucel HF)                                                                   polyethylene glycol monolaurate                                                                     5.0 g                                                   demineralised water   84.0 g                                                  ______________________________________                                    

PREPARATION

The constituents are dissolved in water, with stirring. A polyester film(Hostaphan, Kalle) is coated with silicone adhesive (Silicon Adhesive355, Dow Corning, 55% solid dissolved in special boiling point petroleumfraction 100-120) using a spreading device and a 150 μm doctor blade,and is then dried (15 minutes, 60° C.). Discs having a diameter of 2.5cm (corresponding to a surface area of 5 cm²) are punched out of anon-woven fabric of viscose, polyamide and polypropylene (Vilmed type M1539, Freudenberg) having a thickness of about 2.7 mm. After these discshave been bonded to the coated side of the polyester film, the abovesolution is metered onto the fabric discs in an amount of 450 mg persystem by means of a micro-metering system. The discs are then coveredwith a silicone-treated polyester film. The individual systems arepunched out using a tool having a diameter of 5 cm, care being taken toensure that the fabric disc charged with the active ingredient solutionis located in the center of the system. The finished systems are packedindividually as described in Example 9.

EXAMPLE 11

Membrane transdermal system, closed by means of a seal seam at the edgeand containing as active ingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid Composition:

    ______________________________________                                        active ingredient      10.0 g                                                 hydroxypropylcellulose (Klucel HF)                                                                   1.0 g                                                  polyethylene glycol monolaurate                                                                      5.0 g                                                  demineralised water    84.0 g                                                 ______________________________________                                    

PREPARATION

The adhesive layer (silicone adhesive, see Example 10) is applied to afluorine-treated polyester film by means of a screen printing processand dried. Application of a heat-sealable non-woven fabric of celluloseand polyester (Sontara Vlies 8412, DuPont) to form a laminate consistingof the peel-off film, the adhesive layer and the fabric. The solution isapplied by means of a micro-metering system to the above laminate(fabric on top) in an amount of 300 mg for a 5 cm² system, a cover filmof a heat-sealable polyester/ethyl vinyl acetate composite foil(Scotchpack 1220, 3M) is drawn over the laminate (ethyl vinyl acetateside towards the solution or fabric), and the system is sealed using asuitable heat-sealing tool (inside diameter 2.5 cm, outside diameter 3.5cm; sealing conditions: 0.5 sec, 170° C.) and then punched out andpacked individually as described in Example 9.

EXAMPLE 12

System analogous to Example 11 Composition:

    ______________________________________                                        active ingredient     10.0 g                                                  hydroxypropylcellulose                                                                              3.0 g                                                   (Klucel HF)                                                                   1-dodecylazacycloheptan-2-one                                                                       5.0 g                                                   (Azone, Nelson Res., Irvine CA)                                               ethanol 50%           84.0 g                                                  ______________________________________                                    

PREPARATION

The constituents are dissolved by stirring. Preparation and packing ofthe systems analogously to Example 11.

EXAMPLE 13

Matrix transdermal system consisting of two layers and containing asactive ingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid

Layer 1: Identical to the matrix of Example 9, the matrix being appliedby means of a 150-250 μm doctor blade (rate of application 30-60 g/m²)to a silicone-treated polyester film (for specifications see Example 9)and covered with a silicone-treated paper foil (temporary covering).

Layer 2: A suitable amount of flux enhancer (e.g. 5-25%1-dodecylazacycloheptan-2-one, Azone) is dissolved in the adhesivecompound specified in Example 9 (dissolved in benzine) or in anothersuitable adhesive (e.g. copolymer based on acrylate esters and vinylacetate, Durotak 280-2516, National Starch & Chemical BV, Zutphen/NL)without the active ingredient. The adhesive is laminated by means of a150-300 μm doctor blade and the intermediate layer is removedcontinuously and discarded. Further processing as in Example 9.

EXAMPLE 14

Matrix transdermal system consisting of two layers and containing asactive ingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid

Layer 1: As Example 13.

Layer 2: A suitable amount of flux enhancer is introduced into acustomary hot-melt adhesive (e.g. acrylate adhesive Durotak 089-1526). Apolyester film is applied with an aluminum foil by means of a hot-meltapplicator at about 140°-160° C. The further processing of layers 1 and2 is carried out as in Example 13.

EXAMPLE 15

Reservoir-type membrane transdermal system, containing as activeingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid

Composition analogous to Example 11.

Onto the membrane side of a laminate consisting of peel-off film(polyester, silicone-treated on one side, thickness about 75 μm;)adhesive (e.g. suitable mixture of polyisobutylene 1200000,polyisobutylene 35000 and polyisobutylene 1200; rate of application40-60 g/m²); regulation membrane (ethyl vinyl acetate containing 6-25%vinyl acetate, preferably 12-18%, thickness about 50 μm) an amount ofabout 100-600 mg, depending on the system area provided, of thereservoir formulation according to Example 18 is metered on a suitableapparatus. Alternatively, the active ingredient, or a portion thereof,can be dissolved or suspended in the adhesive layer. In that case, theactive ingredient contained in the adhesive layer would act as theinitial dose and that in the reservoir as the maintenance dose.

In a manner analogous to that described in any one of the aboveExamples, it is possible to incorporate into the base layers otheractive ingredients of formula I, for example selected from4-amino-1-hydroxybutane-1,1-diphosphonic acid,6-amino-1-hydroxyhexane-1,1-diphosphonic acid,3-(N-methyl-N-n-pentyl-amino)-1-hydroxypropane-1,1-diphosphonic acid,3-[N-(3-phenylpropyl)-N-methyl-amino]-1-hydroxypropane-1,1-diphosphonicacid,3-(N-methyl-N-5-phenylpentylamino)-1-hydroxypropane-1,1-diphosponicacid, 3-[N-methyl-N-3-(2-pyridyl)-propylamino]-1-hydroxypropane-1,1-diphosphonic acid,1-hydroxy-3-[N-methyl-N-(3phenoxypropyl)-amino]-propane-1,1-diphosphonicacid,1-hydroxy-3-[N-methyl-N-(2phenoxyethyl)-amino]-propane-1,1-diphosphonicacid, 4-(4-phenyl-piperidin-1-yl)-1-hydroxybutane-1,1-diphosphonic acid,1-hydroxy-3-(1-piperidino)propane-1,1-diphosphonic acid,1-hydroxy-3-[3-(4-chlorophenyl)-pyrrolidin-1-yl]-propane-1,1-diphosphonicacid, 1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid,2-(1-methylimidazol-2-yl)-ethane-1,1-diphosphonic acid,1-hydroxy-2-(4-methylimidazol-5-yl)-ethane-1,1-diphosphonic acid,1-hydroxy-2-(3-pyridyl)-ethane-1,1-diphosphonic acid,2-(2-pyridyl)-ethane-1,1-diphosphonic acid,1-[(5-n-butyl-2-thiazolyl)-amino]-methane-1,1-diphosphonic acid,1-[(5-methyl-2-thiazolyl)-amino]-methane-1,1-diphosphonic acid,1-[(2-thiazolyl)-amino]-methane-1,1-diphosphonic acid1-hydroxyethane-1,1-diphosphonic acid,1-(4-chlorophenylthio)-methane-1,1-diphosphonic acid,1,1-dichloromethane-1,1-diphosphonic acid or3-(1,5-dimethyl-3-azabicyclo[3.1.1]-hept-3-yl)-1-hydroxypropane-1,1-diphosphonicaicd, and also 1-[(5-ethyl-2-thiazolyl)amino]-methane-1,1-diphosphonicacid,3-[N-(2-phenylethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonicacid,3-[N-(2-phenylthioethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonicacid, 1-hydroxy-3-(pyrrolidin-1-yl)-propane-1,1-diphosphonic acid or2-(N-cycloheptylamino)-ethane-1,1-diphosphonic acid, or apharmaceutically acceptable salt thereof.

What is claimed is:
 1. A multilayered transdermal system containing apharmaceutically acceptable methanediphosphonic acid derivative offormula ##STR3## or a salt thereof, wherein each of R₁ and R₂ ishalogen, or wherein R₁ is hydrogen and R₂ is Ar--S--or Het₁ --NH--, inwhich Ar is unsubstituted or substituted phenyl and Het₁ isunsubstituted or substituted, monocyclic, 5- or 6-membered monoaza-,diaza- or thiaza-aryl that is bonded via a ring carbon atom, or whereinR₁ is hydrogen or hydroxy andR₂ is --A--R₃, in which A is alkylene andR₃ is (a) Het₂, which is Het₁ bonded via a ring carbon or ring nitrogenatom, or (b) hydrogen, or amino that is unsubstituted or mono- ordi-substituted by identical or different substituents selected fromalkyl, cycloalkyl, Ar-alkyl, Ar-O-alkyl, Ar-S-alkyl and Het₁ -alkyl, orthat is disubstituted by optionally Ar-containing alkylene, wherein twoalkylene carbon atoms may additionally be linked to one another viaalkylene and Ar and Het₁ are each as defined above, with the provisothat when R₂ is --A--R₃, A is ethylene and R₃ is unsubstituted or C₁ -C₃alkyl-substituted amino, R₁ is other than hydroxy.
 2. The systemaccording to claim 1, containing a compound of formula I or a saltthereof,wherein each of R₁ and R₂ is halogen, or wherein R₁ is hydrogenand R₂ is Ar--S-- or Het₁ --NH--, in which Ar is unsubstituted orsubstituted phenyl and Het₁ is unsubstituted or substituted, monocyclic,5- or 6-membered monoaza-, diaza- or thiaza-aryl that is bonded via aring carbon atom, or wherein R₁ is hydrogen or hydroxy and R₂ is--A--R₃, in which A is alkylene and (a) R₃ is Het₂, which is Het₁ bondedvia a ring carbon or ring nitrogen atom, or (b) R₃ is hydrogen, or aminothat is unsubstituted or mono- or di-substituted by identical ordifferent substituents selected from alkyl, Ar-alkyl, Ar-O-alkyl andHet₁ -alkyl, or that is di-substituted by optionally Ar-containingalkylene, wherein two alkylene carbon atoms may additionally be linkedto one another via alkylene and Ar and Het₁ are each as defined above.3. The system according to claim 1, containing a compound of formula Ior a salt thereof,wherein each of R₁ and R₂ is halogen, or wherein R₁ ishydrogen and R₂ is Ar--S-- or Het₁ --NH--, in which Ar is phenyl that isunsubstituted or substituted by lower alkyl, lower alkoxy,trifluoromethyl and/or halogen, and Het₁ is unsubstituted or loweralkyl-substituted thiazolyl, or wherein R₁ is hydrogen or hydroxy and R₂is --A--R₃, in which A is lower alkylene and (a) R₃ is unsubstituted orlower alkyl-substituted imidazolyl that is bonded via a ring carbon orring nitrogen atom, or is pyridyl, or (b) R₃ is hydrogen, or amino thatis unsubstituted or mono- or di-substituted by identical or differentsubstituents selected from lower alkyl, C₃ -C₇ -cycloalkyl, Ar-loweralkyl, Ar-O-lower alkyl and pyridyl-lower alkyl, or that isdisubstituted by optionally Ar-containing lower alkylene or by loweralkylene wherein two non-adjacent lower alkylene carbon atoms areadditionally linked to one another via lower alkylene, and Ar in eachcase is as defined above.
 4. The system according to claim 1, containinga compound of formula I or a salt thereof, wherein R₁ is hydrogen orhydroxy and R₂ is --A--R₃, in which A is lower alkylene and R₃ is aminothat is mono- or di-substituted by identical or different substituentsselected from lower alkyl, Ar-lower alkyl, C₃ -C₇ -cycloalkyl,Ar-O-lower alkyl, Ar-S-lower alkyl and pyridyl-lower alkyl.
 5. Thesystem according to claim 1, containing a compound of formula I or asaltwherein each of R₁ and R₂ is halogen, or wherein R₁ is hydrogen andR₂ is phenylthio that is unsubstituted or substituted by halogen, orthiazolylamino that is unsubstituted or substituted by lower alkyl, orwherein R₁ is hydrogen or hydroxy and R₂ is --A--R₃ in which A is C₁ -C₇alkylene and R₃ is imidazolyl that is bonded via a ring carbon or ringnitrogen atom and is unsubstituted or substituted by lower alkyl, or ispyridyl, wherein R₁ is hydroxy and R₂ is --A--R₃ in which A is asdefined above and R₃ is amino, di-C₁ -C₅ alkylamino, N-C₁ -C₄alkyl-N-phenyl-C₁ -C₅ alkylamino, N-C₁ -C₄ alkyl-N-pyridyl-C₁ -C₄alkylamino, C₄ -C₆ alkyleneamino that is unsubstituted or substituted byphenyl which may contain halogen, or 1,5-di-C₁ -C₄ alkyl-, or wherein R₁is hydroxy and R₂ is --A--R₃ in which A is C₁ -C₄ alkylene and R₃ ishydrogen.
 6. The system according to claim 1, containing a compound offormula I or a salt thereof,wherein R₁ is hydrogen or hydroxy and R₂ is--A--R₃, in which A is C₁ -C₇ alkylene, and R₃ is N-C₃ -C₇-cycloalkylamino, or N-C₁ -C₄ alkyl-N-phenylthio-C₁ -C₄ alkyl.
 7. Thesystem according to claim 1, containing a compound of formula I or asaltwherein R₁ is hydroxy and R₂ is --A--R₃, in which A is C₂ -C₇alkylene, and R₃ is amino, di-C₁ -C₄ alkylamino, or N-C₁ -C₄alkyl-N-phenyl-C₁ -C₄ alkylamino.
 8. The system according to claim 1,containing a compound of formula I or a salt thereof,wherein R₁ ishydroxy and R₂ is --A--R₃, in which A is C₁ -C₇ alkylene, and R₃ isimidazolyl that is bonded via a ring carbon or ring nitrogen atom and isunsubstituted or substituted by C₁ -C₄ alkyl.
 9. The system according toclaim 1, containing a pharmaceutically effective methanediphosphonicacid selected from the following compounds of formula I:4-amino-1-hydroxybutane-1,1-diphosphonic acid,6-amino-1-hydroxyhexane-1,1-diphosphonic acid,3-(N-methyl-N-n-pentylamino)-1-hydroxypropane-1,1-diphosphonic acid,3-[N-(3-phenylpropyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonicacid,3-(N-methyl-N-5-phenylpentylamino)-1-hydroxypropane-1,1diphosphonicacid,3-[N-methyl-N-3-(2-pyridyl)-propylamino]-1-hydroxypropane-1,1-diphosphonicacid,1-hydroxy-3-[N-methyl-N-(3-phenoxypropyl)-amino]-propane-1,1-diphosphonicacid,1-hydroxy-3-[N-methyl-N-(2-phenoxyethyl)-amino]-propane-1,1-diphosphonicacid,4-(4-phenylpiperidin-1-yl)-1-hydroxybutane-1,1-diphosphonic acid,1-hydroxy-3-(1-piperidino)-propane-1,1-diphosphonic acid,1-hydroxy-3-[3-(4-chlorophenyl)-pyrrolidin-1-yl]-propane-1,1-diphosphonicacid, 1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid,2-(1-methylimidazol-2-yl)-ethane-1,1-diphosphonic acid,1-hydroxy-2-(4-methylimidazol-5-yl)-ethane-1,1-diphosphonic acid,1-hydroxy-2-(imidazol-5-yl)-ethane-1,1-diphosphonic acid,1-hydroxy-2-(3-pyridyl)-ethane-1,1-diphosphonic acid,2-(2-pyridyl)-ethane-1,1-diphosphonic acid,1-[(5-n-butyl-2-thiazolyl)-amino]-methane-1,1-diphosphonic acid,1-[(5-methyl-2-thiazolyl)-amino]-methane-1,1-diphosphonic acid,1-[(2-thiazolyl)-amino]-methane-1,1-diphosphonic acid,1-hydroxyethane-1,1-diphosphonic acid,1-(4-chlorophenylthio)-methane-1,1-diphosphonic acid,1,1-dichloromethane-1,1-diphosphonic acid, or3-(1,5-dimethyl-3-azabicyclo[3.1.1]hept-3-yl)-1-hydroxypropane-1,1-diphosphonicacid, or a pharmaceutically acceptable salt thereof.
 10. The systemaccording to claim 1, containing a pharmaceutically effectivemethanediphosphonic acid selected from the following compounds offormula I:1-[(5-ethyl-2-thiazolyl)-amino]-methane-1,1-diphosphonic acid,3-[N-(2-phenylethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonicacid and3-[N-(2-phenylthioethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonicacid, 1-hydroxy-3-(pyrrolidin-1-yl)-propane-1,1-diphosphonic acid and2-(N-cycloheptylamino)-ethane-1,1-diphosphonic acid, or apharmaceutically acceptable salt thereof.
 11. The system according toclaim 2, containing 1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonicacid or a pharmaceutically acceptable salt thereof.
 12. The systemaccording to claim 1, wherein the multi-layered therapeutic systems fortransdermal administration contain the following constituents:(1) aclosed backing foil which is impermeable to the subsequent layers of theconstituents of the active ingredient formulation, (2) a reservoir forthe active ingredient, next to the backing foil, provided that theactive ingredient is not already present in the adhesive layer, (3) anadhesive layer and (4) a peel-off protecting foil.
 13. A method for thetreatment of hypercalcaemia and osteolytic bone metastases whichcomprises transdermally administering to a warm-blooded animal in needthereof a compound as claimed in claim 1 via the system of claim 1.